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StrokePhase 3WAKE-UPNCT01525290

Efficacy and Safety of MRI-based Thrombolysis in Wake-up Stroke

A Phase 3 study testing Alteplase in people with Stroke, run by Universitätsklinikum Hamburg-Eppendorf at 7 sites in 6 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

WAKE-UP is an investigator initiated European multicenter randomized controlled clinical trial of MRI based thrombolysis in acute stroke patients with unknown time of symptom onset, e.g. due to recognition of stroke symptoms on awakening. Read more about this study

Who is it for?
Ages 18 to 80 years
Conditions the study is for
Stroke
What is being tested?
Alteplase
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
501 participants
Where
7 sitesin 6 countries
Study dates
Sep 2012to Oct 2018
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Clinical Inclusion Criteria
  • Clinical diagnosis of acute ischemic stroke with unknown symptom onset (e.g., stroke symptoms recognized on awakening)
  • Last known well (without neurological symptoms) > 4.5 hours of treatment initiation
  • Measurable disabling neurological deficit (defined as an impairment of one or more of the following: language, motor function, cognition, gaze, vision, neglect)
  • Age 18-80 years
  • Treatment can be started within 4.5 hours of symptom recognition (e.g., awakening)
Show all 10Show fewer
  • Written informed consent by patient or proxy
  • Imaging Inclusion Criteria:
  • Acute stroke MRI including diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) completed
  • MRI showing a pattern of "DWI-FLAIR-mismatch", i.e. acute ischemic lesion visibly on DWI ("positive DWI") but no marked parenchymal hyperintensity visible on FLAIR ("negative FLAIR") indicative of an acute ischemic lesion ≤4.5 hours of age

Who cannot join

  • Clinical Exclusion Criteria
  • Planned or anticipated treatment with endovascular reperfusion strategies (e.g. intra-arterial thrombolysis, mechanical recanalization techniques)
  • Pre-stroke disability (inability to carry out all daily activities, requiring some help or supervision, i.e. slight disability corresponding to an MRS score > 1)
  • Participation in any investigational study in the previous 30 days
  • Severe stroke by clinical assessment (e.g. NIHSS > 25)
  • Hypersensitivity to Alteplase or any of the excipients
Show all 34Show fewer
  • Pregnancy or lactating (formal testing needed in woman of childbearing potential; childbearing potential is assumed in women up to 55 years of age)
  • Significant bleeding disorder at present or within past 6 months
  • Known haemorrhagic diathesis
  • Manifest or recent severe or dangerous bleeding
  • Known history of or suspected intracranial haemorrhage
  • Suspected subarachnoid haemorrhage (even if CT is negative) or condition after subarachnoid haemorrhage from aneurysm
  • History of CNS damage (e.g. neoplasm, aneurysm, intracranial or spinal surgery)
  • Recent (within 10 days) traumatic external heart massage, obstetrical delivery, recent puncture of a non-compressible blood-vessel
  • Current use of anticoagulants (e.g. Phenprocoumon, Warfarin, new anticoagulants such as Dabigatran) or current use of heparin and elevated thromboplastin time (low-dose subcutaneous heparin is allowed)
  • Platelet count < 100.000/mm3 (<100G/l)
  • Blood glucose < 50 or > 400 mg/dl (< 2.8 or 22.2 mmol/l)
  • Severe uncontrolled hypertension, i.e. systolic blood pressure > 185 mmHg or diastolic blood pressure >110 mmHg or requiring aggressive medication to maintain blood pressure within these limits (routine medical treatment is allowed to lower the blood pressure below these limits)
  • Manifest or recent bacterial endocarditis, pericarditis
  • Manifest or recent acute pancreatitis
  • Documented ulcerative gastrointestinal disease during the last 3 months, oesophageal varices, arterial aneurysm, arterial/venous malformations
  • Neoplasm with increased bleeding risk
  • Manifest severe liver disease including hepatic failure, cirrhosis, portal hypertension and active hepatitis
  • Major surgery or significant trauma in past 3 months
  • Stroke within 30 days
  • Life expectancy 6 months or less by judgement of the investigator
  • Any condition associated with a significantly increased risk of severe bleeding not mentioned above
  • Any contraindication to MRI (e.g. cardiac pacemaker)
  • Imaging Exclusion Criteria:
  • Poor MRI quality precluding interpretation according to the study protocol
  • Any sign of intracranial haemorrhage on baseline MRI
  • FLAIR showing a marked parenchymal hyperintensity in a region corresponding to the acute DWI lesion indicative of an acute ischemic lesion with a high likelihood of being > 4.5 hours old
  • Large DWI lesion volume > 1/3 of the MCA or > 50% of the anterior cerebral artery (ACA) or posterior cerebral artery (PCA) territory (visual inspection) or > 100 ml
  • Any MRI findings indicative of a high risk of symptomatic intracranial haemorrhage related to potential IV-tPA treatment in the judgement of the investigator

Trial locations and contacts

7 sites in 6 countries.

7 sites in 6 countries

Germany2 sites

  • Charite - Universitätsmedizin Berlin

    Berlin, 10117

  • University Medical Center Hamburg-Eppendorf

    Hamburg, 20246

Other trials in Germany

Belgium1 site

  • Katholieke Universitet Leuven

    Leuven, 3000

Other trials in Belgium

Denmark1 site

  • Aarhus Universitetshospital, Aahrhus Sygehus

    Aarhus, 8000

Other trials in Denmark

France1 site

  • Hospices Civils de Lyon

    Bron, 69677

Other trials in France

Spain1 site

  • Institut d'Investigacio Biomedica de Girona Doctor Josep Trueta

    Girona, 17007

Other trials in Spain

United Kingdom1 site

  • University of Glasgow

    Glasgow, G12 8QQ

Other trials in United Kingdom

About this study

Official title: Efficacy and Safety of MRI-based Thrombolysis in Wake-up Stroke: a Randomised, Double-blind, Placebo-controlled Trial

WAKE-UP is an investigator initiated European multicenter randomized controlled clinical trial of MRI based thrombolysis in acute stroke patients with unknown time of symptom onset, e.g. due to recognition of stroke symptoms on awakening. Objective of WAKE-UP is to prove efficacy and safety of MRI-based intravenous thrombolysis with Alteplase in patients waking up with stroke symptoms or patients with otherwise unknown symptom onset.

Read the detailed description

WAKE-UP is a clinical trial of MRI based thrombolysis in acute stroke patients with unknown time of symptom onset, e.g. due to recognition of stroke symptoms on awakening. Intravenous thrombolysis with Alteplase is available as effective and safe treatment of acute stroke within 4.5 hours of symptom onset. However, in about 20% of acute stroke patients time of symptom onset is unknown. This large group of patients is currently excluded from treatment with Alteplase. The objective of the research proposed in the WAKE-UP project is to provide effective treatment options for this large group of acute stroke patients.

WAKE-UP is designed to prove efficacy and safety of MRI-based intravenous thrombolysis with Alteplase in patients waking up with stroke symptoms or patients with otherwise unknown symptom onset. Patients will be enrolled based on MRI findings indicative of acute ischemic stroke less than 4.5 hours of age.

Conditions
Stroke
Being tested
Alteplase, Placebo
Keywords
wake-up stroke, thrombolysis, magnetic resonance imaging (MRI), diffusion weighted imaging (DWI), fluid attenuated inversion recovery (FLAIR)
Medical subject headings
Stroke, Ischemic Stroke

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AlteplaseDrug

    Also called Actilyse, Activase, rt-PA

    Intravenous tissue plasminogen activator (Alteplase) 0.9 mg/kg body-weight up to a maximum of 90 mg, 10% as bolus, 90% over 1 hour as infusion

  • PlaceboDrug

    lyophilised powder to be reconstituted as solution indistinguishable from the active drug

Study groups in NCT01525290
Study groupRoleWhat they receive
intravenous tissue plasminogen activatorExperimentalIntervention drug: intravenous tissue plasminogen activator (tPA), alteplase
Receives: Drug: Alteplase
PlaceboPlacebo comparatorIntervention drug: placebo
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Efficacy

    Favourable outcome (Modified Rankin Scale 0-1)

    Measured: 90 day after stroke

  2. Safety

    • Mortality
    • Death or dependency (Modified Rankin Scale 4-6)

    Measured: 90 day after stroke

Secondary outcomes (2)

  1. Efficacy

    • Global outcome score
    • Responder analysis (Modified Rankin Scale 0, 0-1 or 0-2 depending on severity of symptoms assessed by the National Institutes of Health Stroke Scale on admission)
    • Outcome across all disability ranges (categorical shift in Modified Rankin Scale score)
    • Infarct volume (measured 22-36 hours after treatment)
    • Functional health status and quality of life
    • Use of health care system resources

    Measured: 90 days after stroke

  2. Safety

    • Symptomatic intracranial haemorrhage (SICH) as defined in SITS-MOST
    • SICH as defined ECASS II
    • SICH as defined in NINDS
    • Parenchymal haemorrhage type 2 (PH-2)

    Measured: 90 days after stroke

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Feb 2012 (estimated)
  2. Study startSep 2012
  3. Primary completionOct 2018
  4. Study completionOct 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
501 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01525290
Sponsor's protocol ID
WAKE-UP
Acronym
WAKE-UP
Status last verified
Oct 2018
First submitted
30 Jan 2012
Last updated
11 Oct 2018
Results posted
No
Data monitoring committee
Yes

Publications

  • Thomalla G, Simonsen CZ, Boutitie F, Andersen G, Berthezene Y, Cheng B, Cheripelli B, Cho TH, Fazekas F, Fiehler J, Ford I, Galinovic I, Gellissen S, Golsari A, Gregori J, Gunther M, Guibernau J, Hausler KG, Hennerici M, Kemmling A, Marstrand J, Modrau B, Neeb L, Perez de la Ossa N, Puig J, Ringleb P, Roy P, Scheel E, Schonewille W, Serena J, Sunaert S, Villringer K, Wouters A, Thijs V, Ebinger M, Endres M, Fiebach JB, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Gerloff C; WAKE-UP Investigators. MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. N Engl J Med. 2018 Aug 16;379(7):611-622. doi: 10.1056/NEJMoa1804355. Epub 2018 May 16.

    PubMed 29766770

  • Nagele FL, Scheldeman L, Wouters A, Heinze M, Petersen M, Schlemm E, Schell M, Ebinger M, Endres M, Fiebach JB, Fiehler J, Galinovic I, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Puig J, Simonsen CZ, Thijs V, Thomalla G, Cheng B. Blood-Brain Barrier Leakage in the Penumbra Is Associated With Infarction on Follow-Up Imaging in Acute Ischemic Stroke. Stroke. 2025 Jul;56(7):1832-1842. doi: 10.1161/STROKEAHA.124.050171. Epub 2025 Apr 17.

    PubMed 40242873

  • Galinovic I, Fiebach JB, Boutitie F, Cheng B, Cho TH, Ebinger M, Endres M, Enzinger C, Fiehler J, Ford I, Gregori J, Gunther M, Lemmens R, Muir KW, Nighoghossian N, Roy P, Simonsen CZ, Thijs VN, Wouters A, Gerloff C, Thomalla G, Pedraza S; for WAKE-UP Investigators. Effect of IV Thrombolysis With Alteplase in Patients With Vessel Occlusion in the WAKE-UP Trial. Neurology. 2025 Jan 28;104(2):e209871. doi: 10.1212/WNL.0000000000209871. Epub 2024 Dec 20.

    PubMed 39705631

  • Frey BM, Shenas F, Boutitie F, Cheng B, Cho TH, Ebinger M, Endres M, Fiebach JB, Fiehler J, Galinovic I, Barow E, Konigsberg A, Schlemm E, Pedraza S, Lemmens R, Thijs V, Muir KW, Nighoghossian N, Simonsen CZ, Gerloff C, Thomalla G; WAKE-UP Investigators. Intravenous Thrombolysis in Patients With White Matter Hyperintensities in the WAKE-UP Trial. Stroke. 2023 Jul;54(7):1718-1725. doi: 10.1161/STROKEAHA.122.040247. Epub 2023 May 25.

    PubMed 37226772

  • Jensen M, Sehner S, Cheng B, Schlemm E, Quandt F, Barow E, Wegscheider K, Boutitie F, Ebinger M, Endres M, Fiebach JB, Thijs V, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Simonsen CZ, Thomalla G, Gerloff C. Patient-Reported Quality of Life After Intravenous Alteplase for Stroke in the WAKE-UP Trial. Neurology. 2023 Jan 10;100(2):e154-e162. doi: 10.1212/WNL.0000000000201375. Epub 2022 Oct 27.

    PubMed 36302662

  • Barow E, Quandt F, Cheng B, Gelderblom M, Jensen M, Konigsberg A, Boutitie F, Nighoghossian N, Ebinger M, Endres M, Fiebach JB, Thijs V, Lemmens R, Muir KW, Pedraza S, Simonsen CZ, Gerloff C, Thomalla G. Association of White Blood Cell Count With Clinical Outcome Independent of Treatment With Alteplase in Acute Ischemic Stroke. Front Neurol. 2022 Jun 13;13:877367. doi: 10.3389/fneur.2022.877367. eCollection 2022.

    PubMed 35769368

  • Schlemm L, Braemswig TB, Boutitie F, Vynckier J, Jensen M, Galinovic I, Simonsen CZ, Cheng B, Cho TH, Fiehler J, Puig J, Thijs V, Fiebach J, Muir K, Nighoghossian N, Ebinger M, Pedraza S, Thomalla G, Gerloff C, Endres M, Lemmens R, Nolte CH; WAKE-UP Investigators. Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial. Neurology. 2022 Jan 18;98(3):e302-e314. doi: 10.1212/WNL.0000000000013055. Epub 2021 Nov 15.

    PubMed 34782419

  • Lettow I, Jensen M, Schlemm E, Boutitie F, Quandt F, Cheng B, Ebinger M, Endres M, Fiebach JB, Thijs V, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Simonsen CZ, Gerloff C, Thomalla G; WAKE-UP Investigators. Serious Adverse Events and Their Impact on Functional Outcome in Acute Ischemic Stroke in the WAKE-UP Trial. Stroke. 2021 Dec;52(12):3768-3776. doi: 10.1161/STROKEAHA.120.033425. Epub 2021 Aug 26.

    PubMed 34433305

  • Barow E, Boutitie F, Cheng B, Cho TH, Ebinger M, Endres M, Fiebach JB, Fiehler J, Nickel A, Puig J, Roy P, Lemmens R, Thijs V, Muir KW, Nighoghossian N, Pedraza S, Simonsen CZ, Gerloff C, Thomalla G. 24-hour blood pressure variability and treatment effect of intravenous alteplase in acute ischaemic stroke. Eur Stroke J. 2021 Jun;6(2):168-175. doi: 10.1177/23969873211014758. Epub 2021 Jun 18.

    PubMed 34414292

  • Scheldeman L, Wouters A, Dupont P, Christensen S, Boutitie F, Cheng B, Ebinger M, Endres M, Fiebach JB, Gerloff C, Muir KW, Nighoghossian N, Pedraza S, Simonsen CZ, Ringelstein EB, Chamorro A, Grond M, Laage R, Schneider A, Thomalla G, Thijs V, Lemmens R. Reversible Edema in the Penumbra Correlates With Severity of Hypoperfusion. Stroke. 2021 Jul;52(7):2338-2346. doi: 10.1161/STROKEAHA.120.033071. Epub 2021 May 13.

    PubMed 33980046

  • Konigsberg A, Sehner S, Arlt S, Cheng B, Simonsen CZ, Boutitie F, Serena J, Thijs V, Ebinger M, Endres M, Fiebach JB, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Gerloff C, Thomalla G; WAKE-UP investigators. Effect of intravenous alteplase on post-stroke depression in the WAKE UP trial. Eur J Neurol. 2021 Jun;28(6):2017-2025. doi: 10.1111/ene.14797. Epub 2021 Mar 22.

    PubMed 33657675

  • Grosch AS, Kufner A, Boutitie F, Cheng B, Ebinger M, Endres M, Fiebach JB, Fiehler J, Konigsberg A, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Siemonsen CZ, Thijs V, Wouters A, Gerloff C, Thomalla G, Galinovic I. Extent of FLAIR Hyperintense Vessels May Modify Treatment Effect of Thrombolysis: A Post hoc Analysis of the WAKE-UP Trial. Front Neurol. 2021 Feb 4;11:623881. doi: 10.3389/fneur.2020.623881. eCollection 2020.

    PubMed 33613422

  • Barow E, Pinnschmidt H, Boutitie F, Konigsberg A, Ebinger M, Endres M, Fiebach JB, Fiehler J, Thijs V, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Simonsen CZ, Gerloff C, Thomalla G, Cheng B; WAKE-UP investigators. Symptoms and probabilistic anatomical mapping of lacunar infarcts. Neurol Res Pract. 2020 Aug 3;2:21. doi: 10.1186/s42466-020-00068-y. eCollection 2020.

    PubMed 33324925

  • Schlemm L, Kufner A, Boutitie F, Nave AH, Gerloff C, Thomalla G, Simonsen CZ, Ford I, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Ebinger M, Endres M. Current Smoking Does Not Modify the Treatment Effect of Intravenous Thrombolysis in Acute Ischemic Stroke Patients-A Post-hoc Analysis of the WAKE-UP Trial. Front Neurol. 2019 Nov 22;10:1239. doi: 10.3389/fneur.2019.01239. eCollection 2019.

    PubMed 31824412

  • Barow E, Boutitie F, Cheng B, Cho TH, Ebinger M, Endres M, Fiebach JB, Fiehler J, Ford I, Galinovic I, Nickel A, Puig J, Roy P, Wouters A, Thijs V, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Simonsen CZ, Gerloff C, Thomalla G; WAKE-UP investigators. Clinical Characteristics and Outcome of Patients with Lacunar Infarcts and Concurrent Embolic Ischemic Lesions. Clin Neuroradiol. 2020 Sep;30(3):511-516. doi: 10.1007/s00062-019-00800-5. Epub 2019 Jun 3.

    PubMed 31161343

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Alteplase in people with Stroke, run by Universitätsklinikum Hamburg-Eppendorf at 7 sites in 6 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 34 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 11 Oct 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in Germany, Belgium, Denmark, France, Spain and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Efficacy (time frame: 90 day after stroke). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01525290, which also lists 18 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Oct 2018.

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